title: A selective M1 and M3 receptor antagonist, penehyclidine hydrochloride, prevents postischemic LTP: involvement of NMDA receptors.
abstract: Our previous and other studies have confirmed that a selective M1 and M3 receptor antagonist, Penehyclidine hydrochloride (PHC), has neuroprotection activity in cerebral ischemia. However, the precise mechanisms of protection of PHC are still elusive. In this study we analyzed PHC-mediated neuroprotection on a model of brain ischemia (oxygen and glucose deprivation), named postischemic LTP (i-LTP). We found that the activation of NMDA receptor was required for the induction of i-LTP. Compared with scopolamine, PHC could prevent it due to selectively blocking M1 receptor, not M2 receptor, to decrease NMDAR activation. Our findings further showed that the inhibition of SK2 channels occluded the prevention of PHC on NMDAR activation. Furthermore, we confirmed that PHC exerted its roles through directly disinhibition of SK2 channels by blocking M1 receptor and subsequent restricting PKC activation. Moreover, our studies further revealed the critical roles of SK2 channels in i-LTP. Thus, the mechanisms of PHC in brain protection may be involved in suppression of NMDAR by regulation of SK2 channels. Our results obtained in effects of PHC on i-LTP further provided a better understanding of the therapy strategy during stroke and identified potential therapeutic targets to prevent development of ischemia.
authors.affiliation: Key Laboratory for Brain Disease Bioinformation of Jiangsu Province, XuZhou Medical College, XuZhou, Jiangsu Province, 221004, People's Republic of China; Department of Pharmacology, Key Laboratory of new drugs and clinical application, XuZhou Medical College, XuZhou, Jiangsu Province, 221004, People's Republic of China.
authors.forename: Teng-Fei
authors.initials: TF
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Shou-Jun
authors.initials: SJ
authors.lastname: Qin
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Jing-Zhi
authors.initials: JZ
authors.lastname: Yan
authors.forename: Xing
authors.initials: X
authors.lastname: Ma
authors.forename: Cheng-Hua
authors.initials: CH
authors.lastname: Zhou
authors.forename: Shu-Ling
authors.initials: SL
authors.lastname: Gu
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011812:Quinuclidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors*; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors
chemical_list: D018696:Neuroprotective Agents; D026902:Potassium Channel Blockers; D011812:Quinuclidines; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D016194:Receptors, N-Methyl-D-Aspartate; D051640:Small-Conductance Calcium-Activated Potassium Channels; C486140:penehyclidine; D012601:Scopolamine; D011493:Protein Kinase C
keywords: NMDA receptor; hippocampus slice; i-LTP; ischemia; muscarinic receptor